, Volume 37, Issue 12, pp 1509–1523 | Cite as

Value Assessment and Quantitative Benefit-Risk Modelling of Biosimilar Infliximab for Crohn’s Disease

  • Heather Catt
  • Keith Bodger
  • Jamie J. Kirkham
  • Dyfrig A. HughesEmail author
Original Research Article


Background and Objective

Regulatory approval of biosimilars often depends on extrapolating evidence from one clinical indication to all of those of the originator biologic. We aimed to develop a quantitative benefit-risk analysis to assess whether the resulting increase in the uncertainty in the clinical performance of biosimilars (i.e. risk) may be countered by their lower pricing (benefit).


A 1-year decision-analytic model was developed for the biosimilar infliximab (Inflectra®) for Crohn’s disease. The perspective was that of the National Health Service in the UK and costs were valued to 2015/16. A hypothetical cohort of biologic-naïve patients with moderate-to-severe Crohn’s disease was simulated through the model. Immunogenicity to infliximab was a key modifier, influencing rates of non-response and infusion reactions. Net health benefit was estimated based on quality-adjusted life-years. A range of sensitivity analyses tested the robustness of the results and explored how the biosimilar price must respond to varying immunogenicity to remain the preferred option.


The base-case analysis predicted a positive incremental net health benefit of 0.04 (95% central range 0.00–0.09) favouring the biosimilar, based on 0.803 quality-adjusted life-years, and costs of £18,087 and £19,176 for the biosimilar and originator, respectively. Two-way sensitivity analyses suggested that if 50% of patients developed antibodies, the value-based price of £410 per vial must be lower than that of the originator (£420), but remain higher than the actual market price (£378).


The model supports the use of Inflecta® for Crohn’s disease in the UK, and provides a framework for the quantitative evaluation of biosimilars in the context of a health technology assessment. Value-based pricing using this methodology could protect health systems from the potential risks of biosimilars where they are untested in the approved populations.



The research was funded by the Medical Research Council North West Hub for Trial Methodological Research (MR/L004933/2-Q28). The funding sponsors had no role in the design and conduct of the study; in the collection, management, analysis and interpretation of the data; or in the preparation, review or approval of the manuscript. Dyfrig A. Hughes acknowledges the support of Health and Care Research Wales as a Senior Research Leader (SRL/15/029).

Data Availability

The datasets generated during the current study and the model underpinning the study are available from the corresponding author on reasonable request.

Author Contributions

HC, DH, KB and JK contributed substantially to the study conception or design, or the acquisition, analysis or interpretation of the data. HC drafted the manuscript and DAH revised it critically for important intellectual content. HC, DH, KB and JK gave final approval of the version to be published. DAH agrees to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Compliance with Ethical Standards

Conflict of Interest

Heather Catt, Jamie J. Kirkham and Dyfrig A. Hughes have no conflicts of interest that are directly relevant to the content of this article. Keith Bodger declares a travel grant from Janssen-Cilag Ltd.


  1. 1.
    Committee for Medicinal Products for Human Use (CHMP). Guideline on similar biological medicinal products CHMP/437/04 Rev 1. 2015. Available at: Accessed 29 July 2019.
  2. 2.
    Food and Drug Administration. Scientific considerations in demonstrating biosimilarity to a reference product. Guidance for Industry. 2015. Available at: Accessed 29 July 2019.
  3. 3.
    Committee for Medicinal Products for Human Use (CHMP). Guideline on similar biological medicinal products containing monoclonal antibodies: non-clinical and clinical issues. EMA/CHMP/BMWP/403543/2010. 2012. Available at: Accessed 29 July 2019.
  4. 4.
    De Mora F. Biosimilar: what it is not. Br J Clin Pharmacol. 2015;80:949–56.PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Prasad V. Non-inferiority trials in medicine: practice changing or a self-fulfilling prophecy? J Gen Intern Med. 2018;33:3–5.PubMedCrossRefGoogle Scholar
  6. 6.
    Stewart A, Aubrey P, Belsey J. Addressing the health technology assessment of biosimilar pharmaceuticals. Curr Med Res Opin. 2010;26:2119–26.PubMedCrossRefGoogle Scholar
  7. 7.
    Mulcahy AW, Hlavka JP, Case SR. Biosimilar cost savings in the United States: initial experience and future potential. Rand Health Q. 2018;7(4):3. Scholar
  8. 8.
    Yoo DH, Hrycaj P, Miranda P, et al. A randomised, double-blind, parallel-group study to demonstrate equivalence in efficacy and safety of CT-P13 compared with innovator infliximab when coadministered with methotrexate in patients with active rheumatoid arthritis: the PLANETRA study. Ann Rheum Dis. 2013;72:1613–20.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Food and Drug Administration. Addendum to primary clinical review. Recommendation on regulatory action. Inflectra. 2016. Available at: Accessed 29 July 2019.
  10. 10.
    Committee for Medicinal Products for Human Use (CHMP). Assessment report. Inflectra. EMA/CHMP/589422/2013. 2013. Available at: Accessed 29 July 2019.
  11. 11.
    Committee for Medicinal Products for Human Use (CHMP). Guideline on the development of new medicinal products for the treatment of Crohn’s disease. CPMP/EWP/2284/99 Rev. 2. 2016. Available at: Accessed 29 July 2019.
  12. 12.
    Ben-Horin S, Heap GA, Ahmad T, et al. The immunogenicity of biosimilar infliximab: can we extrapolate the data across indications? Expert Rev Gastroenterol Hepatol. 2015;9:27–34.PubMedCrossRefGoogle Scholar
  13. 13.
    Ben-Horin S, Vande Casteele N, Schreiber S, Lakatos PL. Biosimilars in inflammatory bowel disease: facts and fears of extrapolation. Clin Gastroenterol Hepatol. 2016;14:1685–96.PubMedCrossRefGoogle Scholar
  14. 14.
    Feagan BG, Choquette D, Ghosh S, et al. The challenge of indication extrapolation for infliximab biosimilars. Biologicals. 2014;42:177–83.PubMedCrossRefGoogle Scholar
  15. 15.
    Weinstein MC, O’Brien B, Hornberger J, et al. Principles of good practice for decision analytic modeling in health-care evaluation: report of the ISPOR Task Force on Good Research Practices-Modeling Studies. Value Health. 2003;6:9–17.PubMedCrossRefGoogle Scholar
  16. 16.
    Stinnett AA, Mullahy J. Net health benefits: a new framework for the analysis of uncertainty in cost-effectiveness analysis. Med Decis Making. 1998;18:S68–80.PubMedCrossRefGoogle Scholar
  17. 17.
    Kaplan GG, Hur C, Korzenik J, Sands BE. Infliximab dose escalation vs. initiation of adalimumab for loss of response in Crohn’s disease: a cost-effectiveness analysis. Aliment Pharmacol Ther. 2007;26:1509–20.PubMedCrossRefGoogle Scholar
  18. 18.
    Roda G, Jharap B, Neeraj N, Colombel J-F. Loss of response to anti-TNFs: definition, epidemiology, and management. Clin Transl Gastroenterol. 2016;7:e135.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Cheifetz A, Smedley M, Martin S, et al. The incidence and management of infusion reactions to infliximab: a large center experience. Am J Gastroenterol. 2003;98:1315–24.PubMedCrossRefGoogle Scholar
  20. 20.
    Gomollón F, Dignass A, Annese V 3rd, et al. 3rd European evidence-based consensus on the diagnosis and management of Crohn’s disease: 2016. Part 1: diagnosis and medical management. J Crohns Colitis. 2016;2017(11):3–25.Google Scholar
  21. 21. Remicade 100 mg powder for concentrate for solution for infusion: summary of product characteristics (SPC). eMC 1–16 (2009). Accessed 25 Jun 2018.
  22. 22.
    Terdiman JP, Gruss CB, Heidelbaugh JJ, Sultan S, Falck-Ytter YT. American gastroenterological association institute guideline on the use of thiopurines, methotrexate, and anti-TNF-α biologic drugs for the induction and maintenance of remission in inflammatory Crohn’s disease. Gastroenterology. 2013;145:1459–63.PubMedCrossRefGoogle Scholar
  23. 23.
    Hanauer SB, Feagan BG, Lichtenstein GR, et al. Maintenance infliximab for Crohn’s disease: the ACCENT I randomised trial. Lancet. 2002;359:1541–9.PubMedCrossRefGoogle Scholar
  24. 24.
    Office for National Statistics. UK life tables 2012–2014. 2016. Available at: Accessed 29 July 2019.
  25. 25.
    Lee LYW, Sanderson JD, Irving PM. Anti-infliximab antibodies in inflammatory bowel disease. Eur J Gastroenterol Hepatol. 2012;24:1078–85.PubMedCrossRefGoogle Scholar
  26. 26.
    Miheller P, Lakatos PL, Horváth G, et al. Efficacy and safety of infliximab induction therapy in Crohn’s Disease in Central Europe: a Hungarian nationwide observational study. BMC Gastroenterol. 2009;9:66.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Nanda KS, Cheifetz AS, Moss AC. Impact of antibodies to infliximab on clinical outcomes and serum infliximab levels in patients with inflammatory bowel disease (IBD): a meta-analysis. Am J Gastroenterol. 2013;108:40–7.PubMedCrossRefGoogle Scholar
  28. 28.
    Saito S, Shimizu U, Nan Z, et al. Economic impact of combination therapy with infliximab plus azathioprine for drug-refractory Crohn’s disease: a cost-effectiveness analysis. J Crohns Colitis. 2013;7:167–74.PubMedCrossRefGoogle Scholar
  29. 29.
    Silverstein MD, Loftus EV, Sandborn WJ, et al. Clinical course and costs of care for Crohn’s disease: Markov model analysis of a population-based cohort. Gastroenterology. 1999;117:49–57.PubMedCrossRefGoogle Scholar
  30. 30.
    O’Meara S, Nanda KS, Moss AC. Antibodies to infliximab and risk of infusion reactions in patients with inflammatory bowel disease: a systematic review and meta-analysis. Inflamm Bowel Dis. 2014;20:1–6.PubMedCrossRefGoogle Scholar
  31. 31.
    Siegel CA, Finlayson SRG, Sands BE, Tosteson ANA. Adverse events do not outweigh benefits of combination therapy for crohn’s disease in a decision analytic model. Clin Gastroenterol Hepatol. 2012;10:46–51.PubMedCrossRefGoogle Scholar
  32. 32.
    Ananthakrishnan AN, Hur C, Juillerat P, Korzenik JR. Strategies for the prevention of postoperative recurrence in Crohn’s disease: results of a decision analysis. Am J Gastroenterol. 2011;106:2009–17.PubMedCrossRefGoogle Scholar
  33. 33.
    Gregor JC, McDonald JWD, Klar N, Wall R, Atkinson K, Lamba B, et al. An evaluation of utility measurement in Crohn’s disease. Inflamm Bowel Dis. 1997;3:265–76.PubMedCrossRefGoogle Scholar
  34. 34.
    Doherty GA, Miksad RA, Cheifetz AS, Moss AC. Comparative cost-effectiveness of strategies to prevent postoperative clinical recurrence of Crohn’s disease. Inflamm Bowel Dis. 2012;18:1608–16.PubMedCrossRefGoogle Scholar
  35. 35.
    Curtis L. PSSR unit costs of health and social care 2013. 2013. Available at: Accessed 29 July 2019.
  36. 36.
    Kasi PM, Tawbi HA, Oddis CV, Kulkarni HS. Clinical review: serious adverse events associated with the use of rituximab: a critical care perspective. Crit Care. 2012;16:231.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Bodger K, Kikuchi T, Hughes D. Cost-effectiveness of biological therapy for Crohn’s disease: Markov cohort analyses incorporating United Kingdom patient-level cost data. Aliment Pharmacol Ther. 2009;30:265–74.PubMedCrossRefGoogle Scholar
  38. 38.
    National Institute for Health and Care Excellence. Infliximab and adalimumab for the treatment of Crohn’s disease—TA187. 2010. p. 1–44. Available at: Accessed 29 July 2019.
  39. 39.
    National Institute for Health and Care Excellence. Ustekinumab for treating moderately to severely active Crohn’s disease after previous treatment—Technology appraisal guidance TA456. 2017. Available at: Accessed 29 July 2019.
  40. 40.
    National Institute for Health and Care Excellence. Vedolizumab for treating moderately to severely active Crohn’s disease after prior therapy: technology appraisal guidance TA352. 2015. Accessed 1 Jul 2018.
  41. 41.
    National Institute for Health and Care Excellence. Guide to the methods of technology appraisal 2013. 2013. Available at: Accessed 29 July 2019.
  42. 42. Humira 40 mg solution for injection in pre-filled syringe: summary of product characteristics (SPC). eMC (2003). Accessed 10 Jul 2018.
  43. 43. STELLARA 90 mg solution for injections: summary of product characteristics (SPC). eMC (2009). Accessed 10 Jul 2018.
  44. 44. Entyvio 300 mg powder for concentrate for solution for infusion: summary of product characteristics (SPC). eMC (2014). Accessed 10 Jul 2018.
  45. 45.
    Sandborn WJ, Hanauer S, Loftus EV Jr, et al. An open-label study of the human anti-TNF monoclonal antibody adalimumab in subjects with prior loss of response or intolerance to infliximab for Crohn’s disease. Am J Gastroenterol. 2004;99:1984–9.PubMedCrossRefGoogle Scholar
  46. 46.
    Da W, Zhu J, Wang L, Lu Y. Adalimumab for Crohn’s disease after infliximab treatment failure. Eur J Gastroenterol Hepatol. 2013;25:885–91.PubMedCrossRefGoogle Scholar
  47. 47.
    Colombel J-F, Sloan S, Gasink C, et al. A147 response and remission after 16 weeks of ustekinumab: an all patients analysis from the UNITI Crohn’s studies. J Can Assoc Gastroenterol. 2018;1(Suppl. 2):219–20.PubMedCentralCrossRefGoogle Scholar
  48. 48.
    Feagan BG, Sandborn WJ, Gasink C, et al. Ustekinumab as induction and maintenance therapy for Crohn’s disease. N Engl J Med. 2016;375:1946–60.PubMedCrossRefGoogle Scholar
  49. 49.
    Sands BE, Feagan BG, Rutgeerts P, et al. Effects of vedolizumab induction therapy for patients with Crohn’s disease in whom tumor necrosis factor antagonist treatment failed. Gastroenterology. 2014;147(618–27):e3.Google Scholar
  50. 50.
    Sandborn WJ, Feagan BG, Rutgeerts P, et al. Vedolizumab as induction and maintenance therapy for Crohn’s disease. N Engl J Med. 2013;369:711–21.PubMedCrossRefGoogle Scholar
  51. 51.
    Strong M, Oakley JE, Brennan A. Estimating multiparameter partial expected value of perfect information from a probabilistic sensitivity analysis sample. Med Decis Making. 2014;34:311–26.PubMedCrossRefGoogle Scholar
  52. 52.
    National Institute for Health and Care Excellence. Infliximab and adalimumab for the treatment of Crohn’s disease costing template and report: technology appraisal guidance 187. 2010. Available at: Accessed 29 July 2019.
  53. 53.
    Husereau D, Drummond M, Petrou S, et al. Consolidated Health Economic Evaluation Reporting Standards (CHEERS): explanation and elaboration. A report of the ISPOR Health Economic Evaluations Publication Guidelines Task Force. Value Health. 2013;16:231–50.PubMedCrossRefGoogle Scholar
  54. 54.
    Lynd LD, O’Brien BJ. Advances in risk-benefit evaluation using probabilistic simulation methods: an application to the prophylaxis of deep vein thrombosis. J Clin Epidemiol. 2004;57:795–803.PubMedCrossRefGoogle Scholar
  55. 55.
    Breeze P, Brennan A. Valuing trial designs from a pharmaceutical perspective using value-based pricing. Health Econ. 2014;18:S37–54.Google Scholar
  56. 56.
    Kim YH, Ye BD, Pesegova M, et al. DOP061 phase III randomised, double-blind, controlled trial to compare biosimilar infliximab (CT-P13) with innovator infliximab in patients with active Crohn’s disease: early efficacy and safety results. J Crohns Colitis. 2017;11:S62.CrossRefGoogle Scholar
  57. 57.
    Fiorino G, Manetti N, Armuzzi A, et al. The PROSIT-BIO Cohort: a prospective observational study of patients with inflammatory bowel disease treated with infliximab biosimilar. Inflamm Bowel Dis. 2017;23:233–43.PubMedCrossRefGoogle Scholar
  58. 58.
    Ben-Horin S, Yavzori M, Benhar I, et al. Cross-immunogenicity: antibodies to infliximab in Remicade-treated patients with IBD similarly recognise the biosimilar Remsima. Gut. 2016;65:1132–8.PubMedCrossRefGoogle Scholar
  59. 59.
    Ye BD, Pesegova M, Alexeeva O, et al. Efficacy and safety of biosimilar CT-P13 compared with originator infliximab in patients with active Crohn’s disease: an international, randomised, double-blind, phase 3 non-inferiority study. Lancet. 2019;393(10182):1699–707.PubMedCrossRefGoogle Scholar
  60. 60.
    Acha V, Mestre-Ferrandiz J. Translating European regulatory approval into healthcare uptake for biosimilars: the second translational gap. Technol Anal Strateg Manag. 2017;29:263–75. Scholar
  61. 61.
    National Institute for Health and Care Excellence. NICE’s biosimilar position statement. 2014; 7–8.Google Scholar
  62. 62.
    Ungar B, Chowers Y, Yavzori M, et al. The temporal evolution of antidrug antibodies in patients with inflammatory bowel disease treated with infliximab. Gut. 2014;63:1258–64.PubMedCrossRefGoogle Scholar
  63. 63.
    Kennedy NA, Heap GA, Green HD, UK Inflammatory Bowel Disease Pharmacogenetics Study Group, et al. Predictors of anti-TNF treatment failure in anti-TNF-naive patients with active luminal Crohn’s disease: a prospective, multicentre, cohort study. Lancet Gastroenterol Hepatol. 2019;4(5):341–53.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.MRC North West Hub for Trials Methodology Research, Department of BiostatisticsUniversity of LiverpoolLiverpoolUK
  2. 2.School of Health Sciences, Division of Population Health, Health Services Research and Primary CareManchester UniversityManchesterUK
  3. 3.Aintree University Hospital NHS TrustDigestive Diseases CentreLiverpoolUK
  4. 4.Centre for Biostatistics, Manchester Academic Health Science CentreUniversity of ManchesterManchesterUK
  5. 5.Centre for Health Economics and Medicines Evaluation, Bangor UniversityBangorUK

Personalised recommendations